Molecular Genetic Testing

This recommendation is quite restrictive despite the extensive genetic information available. The rationale for the strength of evidence is derived largely from the published sensitivity of genetic testing, as presented in Tables 17.1, 17.2 and 17.3. These recommendations do not address molecular testing in prenatal, newborn screening or in-vitro fertilization settings. Additional information for specific genes or genetic diagnoses are available at the Online Mendelian Inheritance in Man (OMIM) website (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim), which can be accessed using OMIM numbers assigned to genes (See Tables 17.1, 17.2 and 17.3) or genetic condition (see Table 17.4) associated with cardiomyopathy.

Recommendation 17.4 states that the individual with the most evident disease should be the individual selected from a family to undergo genetic testing. This is a well established principle in clinical genetics, as selecting the individual with the most evident disease that has been clinically confirmed to a high degree of certainty decreases the probability of testing a phenocopy (someone who clinically has the disease from another cause and does not carry the family mutation) and thereby increases the likelihood of finding a genetic cause. Usually the individual with more evident disease will also provide a more compelling phenotype, typically with more disease features, enabling the most accurate classification of the cardiomyopathy. Procurement of a tissue sample (preferentially tissue that has not been fixed) from an autopsy specimen can provide DNA for genetic testing. At times a DNA-containing sample from the family member with the most evident disease is not available, commonly because of death antecedent to the genetic analysis. Thus, another individual from the family must be selected for testing. Selection of a secondary individual for testing requires careful consideration, especially because of the low sensitivity for genetic testing for many cardiomyopathies. The professional selecting the individual for testing will need to consider the implications of negative genetic test results for that subject and have a plan for any additional testing for the remaining at-risk family members. On the other hand, if a mutation can be identified and the evidence supports its role as the disease-causing mutation, testing can be performed in relatives regardless of their clinical status.

Recommendation 17.4 also restricts the indication for genetic testing to that of facilitation of family screening and management. Simply put, this recognizes that currently the primary value, the primary reason to seek genetic testing for the genetic cardiomyopathies, is to more accurately predict the risk of a family member developing cardiomyopathy who currently has little or no clinical evidence of cardiovascular disease.

If a disease-causing mutation is identified in the affected family member initially tested, and subsequent genetic testing of an at-risk but presymptomatic family member is negative, that family member's risk of developing the cardiomyopathy is substantially reduced. In this situation the need for ongoing clinical screening in such a mutation-negative family member is not recommended. On the other hand, if a disease-causing mutation is identified in an asymptomatic, at-risk family member, the confidence is much greater to infer risk for that individual. The individual should be counseled on the presenting signs and symptoms of the specific cardiomyopathy, the associated reduced penetrance and variable expressivity, and the rationale and frequency of the recommended clinical surveillance.

Notably these recommendations are silent for any additional interventions specific for a disease-causing mutation. The reason for this stems from the lack of validated genotype-phenotype correlations of specific mutations with specific clinical cardiovascular outcomes. Unless or until specific mutations have been shown to reliably predict specific clinical outcomes (eg, increased or reduced risk of a specific event such as the development of symptomatic heart failure or the high probability of sudden cardiac death), the recommendations will refer to the general behavior of each disease gene.

The general characteristics of disease presentation and progression may suggest involvement of specific genes. We refer to this as 'gene-phenotype relationships' in contrast to the more commonly used 'genotype-phenotype relationships,' commonly used to indicate phenotypic characteristics of specific mutations. The strongest evidence for gene-phenotype relationships is present for HCM and DCM (Table 17.5).

Recommendation 17.4, focused on genetic testing to facilitate family screening and management, is also silent for specific recommendations for apparent sporadic (non-familial) disease. However, considerable evidence suggests that HCM results from both sporadic and familial genetic disease.11 In contrast, the etiology of DCM that does not appear to be familial remains enigmatic, as is the evidence to support an underlying genetic cause. Some patients with DCM, but without a positive family history, have been shown to harbor mutations consistent with genetic causation of their disease (Table 17.2). Further, the largest genetic survey to date of six DCM disease genes in 313 unrelated probands observed a similar frequency of mutations attributed to familial vs sporadic disease.19 However, patient acquisition for that study was not specifically designed to address the frequency of the genetic basis of sporadic DCM versus familial disease, and familial disease was not excluded with prospective clinical screening of first-degree relatives in those assigned to have sporadic DCM. This is particularly relevant, as conducting clinical screening of first-degree family members with echocardiograpy and ECG has been shown to have four-fold greater sensitivity to detect familial DCM compared to obtaining a careful 3-generation family history.20 Thus, a genetic etiology for the bulk of non-ischemic, presumably non-familial (sporadic) DCM, while plausible, is not yet supported by rigorous studies that provide robust, reliable estimates of the frequency of genetic causation.

HCM has the strongest evidence to support genetic testing (Table 17.1). ARVD/C, although quite rare, also has good evidence to support genetic testing (Table 17.3).

Testing for DCM is confounded by the question of etiology of sporadic DCM discussed above. It is also greatly confounded by the extensive genetic heterogeneity, as well as the relatively low frequency of involvement of any one gene in DCM. Technological advances will continue to improve testing methods, thereby dramatically decreasing costs. While such progress will make it possible to test many DCM genes simultaneously, it is likely that sequence variations of unknown significance will be discovered that may confound test interpretation.

However, testing for the LMNA gene is recommended in patients with prominent conduction disease with or without supraventricular or ventricular arrhythmias (Table 17.5), or with signs of skeletal muscle involvement, shown most commonly by elevated creatine kinase (CK-MM) because in both groups LMNA mutations appear to be at higher frequency (Table 17.5). LMNA molecular genetic testing may be considered for all DCM patients based on its overall higher frequency in DCM (Table 17.5: a mean of 7.3% of those with familial disease, or 3.0% of those with apparent sporadic disease, or 5.5% overall, as summarized from six studies 21-26), and because of its diagnosis on prognosis and management.27

Data are only now emerging describing the genetic basis of LVNC, limiting strength of recommendations, as is the case for RCM (Table 17.3).

Clinical genetic testing should be carried out in a fully accredited molecular genetic testing laboratory that has met Clinical Laboratory Improvement Amendment (CLIA) standards. Clear distinctions should be made between testing for clinical purposes, as advocated by these recommendations, in CLIA-accredited laboratories and that undertaken for research purposes that cannot be used to direct clinical care (unless conducted in a CLIA-certified research laboratory that provides clinical reports). Because the genetic knowledge base of cardiomyopathy is still emerging, practitioners caring for patients and families with genetic cardiomyopathy are encouraged to consider research participation. Referral centers expert in genetic cardiomyopathy are experienced in explaining the roles and outcomes of clinical testing versus research participation, which may include research genetic testing, and are able to facilitate both objectives.28